Barriers, pores, pumps and gates;

In the beginning...

The earliest 'living' things on the planet were self-replicating molecules which floated around in a primeval soup busily replicating. Isolated molecules have no internal environment and so are unable to indulge in homeostasis. However, at some point these self-replicating molecules 'discovered' a way to isolate themselves from their immediate environment. If you live in a watery environment and you want a little isolation, a fat bubble is what you need, because fat or oil and water don't mix, so a fat or lipid layer will act as an effective barrier to the outside world. Once contained within a fat bubble the self-replicating molecules had an internal environment that they could regulate to suit themselves. At this point we can pass over several hundred million years of evolution and call these thing 'cells'. A cell is a collection of self-replicating molecules (DNA) surrounded by a fat bubble (the plasma membrane).

Channels and pores.

A simple, completely exclusive barrier between the intracellular and extracellular environments is not by itself much use in homeostasis. The barrier with the outside world must allow in those things necessary or growth and development whilst excluding everything else. In short it must be selectively permeable. Pure lipid would be impermeable to most water-soluble substances so a plasma membrane contains channels and pores built from protein molecules to enable selected substances to enter (or leave) the cell. A pore or channel is a protein with a hydrophobic (water hating, lipid loving) exterior which can sit happily in the membrane and a hydrophilic (water loving) centre through which water and small water soluble molecules can pass. If such a molecule is inserted into a plasma membrane so that one end sticks out of the cell and the other end sticks out into the cell interior water soluble compounds can cross the membrane without ever coming into contact with the lipid. A plasma membrane almost always includes water, K+, Cl- and Ca2+ channels; many cell types also have Na+ channels. Ion channels are also (usually) gated i.e. they may be open or closed.

In general, O2 and CO2 and non-polar solutes such as urea can diffuse into and out of cells across the lipid of the plasma membrane. Water and ions can only diffuse in and out of cells through a channel or pore (and only then if the channel is open). Ion channels are present in all plasma membranes but they will be open or closed depending on the needs and the function of the cell.

Diffusion and the electrochemical gradient

Channels and pores can exclude a molecule from the cell or keep something inside the cell by being closed (or by not being present, i.e. Na+ cannot cross the cell membrane if it does not contain Na+ channels). If the channel is present and it is open, then the permeating substance can pass through the channel down its concentration gradient, from a region of high concentration to a region of low concentration (diffusion).

If the substance crossing the membrane is charged (e.g. an ion such as K+ or Na+) and there is an electrical potential difference across the plasma membrane (which there is) then the electrical potential will also drive the substance across the membrane. The chemical driving force (of the concentration gradient) and the electrical driving force (of the membrane potential) add algebraically to give the electrochemical driving force. The electrical and chemical components of the electrochemical gradient can operate in the same direction to create an electrochemical gradient that is the sum of both of them. Or, if the concentration (chemical) gradient is pushing one way and the electrical gradient is pushing the other way then they cancel each other out either partially or completely (the electrochemical gradient is zero). It follows that for every permeable ion there is a membrane potential, which will exactly balance the concentration gradient for that ion. This membrane potential is known as the equilibrium or Nernst potential and it may be calculated using the Nernst equation.

Just to make things really complicated, it is the diffusion of ions that creates the membrane potential in the first place. Imagine a cell membrane permeable only to K+ and further imagine that there is a 10 fold K+ gradient running from the inside of the cell (100 mmol/l) to outside the cell (10 mmol/l). Potassium will diffuse down the concentration gradient and out of the cell. However, every time a positively charged potassium ion crosses the membrane it makes the inside of the cell membrane a little more negatively charged (The positive charge is being lost to the cell. This negative charge will try to attract positively charged K+ back into the cell, or at least try to prevent further K+ loss). The build up of negative charge on the inside of the membrane is the membrane potential. Assuming that no other ion can cross the membrane, the potential will build up until it acts as a driving force exactly equal and opposite to that of the chemical gradient. The cell membrane potential will be exactly equal to the equilibrium potential for potassium. At this point there will be no further net movement of potassium.

If any ion other than potassium is allowed to cross the membrane then the membrane potential will also depend on the concentration gradient (and the relative permeability) of that ion. A useful way of thinking about the membrane potential is to consider that it is created by K+ movement and that it can then drive the movement of other ions. This is nearly true for most cells.

 

There can be no net movement of a substance through a channel or pore against its electrochemical gradient.

 

Active Transport

Cells do move substances across the plasma membrane against their electrochemical gradients, not through channels or pores but by active transport. Moving against an electrochemical gradient requires an input of energy in order to overcome the gradient (just as a car can free wheel down hill but needs an engine to get back up again). Active transporters are enzymes that utilise metabolic energy in order to 'pump' against an electrochemical gradient.

 

Primary active transport

Perhaps the most straightforward type of active transport is primary active transport in which metabolic energy in the form of ATP is directly utilised by an enzyme to move a substance across a membrane. The most ubiquitous and widely known example of primary active transport process is the sodium pump, or sodium / potassium ATPase. The Na+ pump uses ATP to extrude Na+ from the cell in exchange for K+ (3Na+ out for 2K+ in). The Na+ pump is therefore responsible for the high K+ concentration found within cells and thus the inside to outside directed K+ gradient that generates the membrane potential. So, although the Na+ pump does not itself create the membrane potential (which is a commonly held misconception) it does maintain it by keeping the intracellular K+ concentration high. There are other actively transporting ATPases. A proton pump pumps protons (H+) out of the cell (sometimes in exchange for Na+). Various different cell types utilise a proton pump, in particular the cells in the stomach which secrete gastric acid and kidney cells which are (partly) responsible for regulating the pH of the whole body. The calcium pump is another important ATPase that is present in one form or another in all cell types. Intracellular calcium concentration is used as an on/off switch for lots of cellular processes. Increase intracellular calcium concentration and lots of Ca2+-dependent enzymes get activated. Reduce intracellular calcium concentration and they all switch off again. The Ca2+-ATPase has a very important part in this process because it is able to maintain intracellular calcium concentrations at very low levels.

The ATPases responsible for primary active transport exist in a variety of different forms, but under physiological conditions the only substances that cross the plasma membrane as the direct result of primary active transport are Na+, Ca2+, K+ and H+. If there is such as a thing as a Cl- pump, then no one has found it yet!

Even though there are very few substrates for primary active transport, there are nevertheless active transport processes for a bewildering variety of substances. Everything else that must be actively transported across the plasma membrane moves by secondary active transport.

 

Secondary Active Transport

Whereas primary active transport makes direct use of metabolic energy in the form of ATP, secondary active transport uses metabolic energy indirectly in the form of a concentration gradient created by a primary active transport process. In other words...... As a direct result of the activity of the Na+ pump intracellular Na+ is low relative to extracellular Na+. There is therefore an inwardly directed Na+ gradient. Just as K+ is keen to leave the cells, so Na+ is desperate to enter. But whereas the cells allow K+ to leave (and thus create the membrane potential) most plasma membranes are practically inpermeant to Na+. So Na+ can't get in, at least not by itself. Secondary active transporters allow Na+ to enter the cell only if accompanied by another substrate. Thus a glucose transporter carries glucose and Na+ into the cell, an amino acid transporter carries amino acids and Na+ into the cell. In effect, the co-transported substrate gets a free ride on the Na+ gradient. So long as the Na+ gradient is bigger than the gradient of the co-transported substrate, whatever it is, will be concentrated inside the cell. This sort of arrangement can work with many different pairs of substrates, but it works especially well with Na+ because the Na+ pump gets rid of the Na+ as soon as it enters the cell and thus preserves the large inwardly directed Na+ gradient. This sort of secondary active transport is known as co-transport because two substances (Na+ and something else) are co-transported together. More properly, it is an example of symport because the two substances are moving in the same direction. Another variant of secondary active transport is antiport where the two substrates move in opposite directions. Sodium proton exchange is an example of this. Sodium moves into the cell in exchange for H+ leaving the cell.

 

In secondary active transport the Na+ gradient is inwardly directed. Sodium always, always, always moves into the cell

 

An individual cell, whether part of an organism or a single cell creature, is able to create and maintain an internal environment by virtue of possessing a lipid based plasma membrane which regulates contact with the extracellular environment. Regulation occurs via channels, pores and transporters. The whole process is driven by metabolic energy in the form of ATP that is utilised by the transport processes either directly as in primary active transport or indirectly as in secondary active transport.

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© Pete Smith 1998